In order to improve the therapeutic safety and efficacy of the immediate release drugs, the sustained-release dosage forms have been developed by the industry. These dosage forms are capable of dampening the peaks and valleys experienced with the immediate release dosage form of drugs. However, the sustained-release dosage forms do not give the ideal zero-order release of drugs in the body. Upon swallowing the sustained-release form of drugs, the drug concentration reaches a maximum value (maximum at time, t.sub.max) and thereafter declines continuously at an exponential rate. Thus the sustained-release dosage forms do not produce a constant level of drug in the body, which is the desirable objective of most drug delivery systems. The ideal zero-order delivery system will release drug at a uniform rate and thus lead to constant drug levels in the body. This will maximize the therapeutic benefit to the subject while minimizing the toxic side effects associated with super therapeutic levels.
Several methods for producing a sustained-release delivery system are known in the art among these are the following.
Film-Coated Beads: Sustained-release drugs are made by encapsulating tiny beads of the drug substance in a semi-permeable membrane. Upon contact with the body fluids, the body fluids diffuse into the drug bead through the semi-permeable membrane and dissolve the drug substance. The solution of the drug dissolved in body fluids (water) then diffuses out through the membrane. The rate of drug diffusion is dependent upon the drug concentration remaining in the bead. As the drug concentration falls, so does the rate of diffusion through the membrane. The rate of release has been reported to be 1st order or declining exponentially with time. The diffusion of active ingredient through a membrane is described by the following equation: where:
M.sub.t /M.sub..infin.=fraction dissolved at time t PA1 k=rate constant PA1 M.sub.t =mass of drug dissolved at time t PA1 M.sub..infin. =mass of drug at time t=0
Dissolution profiles for film-coated beads show exponentially declining release rate profiles as stated by above equation.
The zero-order release kinetics is described by the following equation, which if satisfied would show that zero-order release has been obtained: ##EQU1## This type of behavior has not been obtained with film-coated beads.
Attempts have been made to overcome this shortcoming of sustained-release drugs and yet very little success has been reported. A survey of patent literature suggests that attempts have been made to improve product release characteristics through use of a variety of polymers and polymer blends. These attempts have not succeeded in obtaining time-independent release rates, because the characteristic Fickian diffusion type of release has been found to predominate in spite of using a variety of polymers and blends.
Matrix Type of Delivery: The matrix type delivery devices consist primarily of an active agent finely dispersed in a monolithic matrix.
A flat slab of an eroding polymer containing a uniformly distributed drug has been reported to give zero-order release. The release kinetics, however, are reported to be dependent upon the system geometry. For sphperical matrices, this system does not give zero-order release.
In the case of a drug homogeneously dispersed in a noneroding matrix, the release rate has been found to be proportional to square root of time (M=kt.sup.1/2, Higuchi Kinetics). More recently, research has focused on use of hydrogels in tablets. Zero-order release has reportedly been obtained through the use of concentration profiling of the drug inside the tablet matrix. (Professor Neil Graham and N. E. McNeill, University of Strathclyde, Glasgow, UK "Principles of the Design of Hydrogel-Containing Programmed Delivery Devices"--13th International Conference on Controlled Release of Bioactive Materials", Aug. 4, 1986, Norfolk, Va.).
Other approaches are also under study which focus on altering the structural characteristics in the hydrogels through cross linking, copolymerization, etc. (Roorda, W. E., et. al--"Zero-Order Release of Oxprenolol-HCl: A New Approach," Center for Bio-Pharmaceutical Sciences, Leyden University, Netherlands, presented at 13th International Conference on Controlled Release of Bioactive Materials, Aug. 4, 1986, Norfolk, Va.). The purpose of this research is to develop new polymers or modify existing ones such that a zero-order release can be obtained.
The present research approaches for matrix type systems appear to rely either on altering the structure of polymers or on the use of concentration profiling.
Reservoir Devices: In this approach, the active agent is uniformly dispersed in a suitable carrier and is encased in a membrane. As long as the active agent is in excess of the maximum solubility in the penetrant fluid, a constant thermodynamic activity is maintained across the outer membrane giving a zero-order release. As the active agent is depleted, the agent dissolves completely in the fluid, its activity falls off with time giving an exponential decline in release rate. (Controlled Release Polymeric Formulations, Paul, D. R. and Harris, F. W., ACS Symposium Series, ACS NY, Apr. 1976, Chapter 1).
Osmotic Devices: Alza company holds numerous patents for zero-order release of a drug via use of osmotic force. Water diffuses from the surrounding media to the tablet core and dissolves the drug. The drug solution does not diffuse out through the one-way membrane. Instead, like a pump, the solution oozes out from a single laser-drilled hole in the tablet under osmotic forces. The release rate is zero-order until 60-70% of the drug is released, followed by a declining rate of release. Alza's technology applies only to tablets and not to microencapsulated beads since it would be very expensive and technically difficult to drill precise holes in the microspheres.
Thus except for reservoir devices, zero-order release has reportedly not been achieved in case of microcapsules. Zero-order release with reservoir devices is obtained until no excess drug is left in contact with a saturated drug solution in the reservoir. A recent paper (M. Donbrow, School of Pharmacy, Jerusalem, Israel presented at the 13th International Symposium on Controlled-Release of Bioactive Materials, Aug. 3-6, 1986--Norfolk, Va.) states "Microcapsule release literature includes many unvalidated reports of exponential release, also some matrix release (M=kt.sup.1/2 or Higuchi Kinetics), and dissolution rate-limiting release (m.sup.1/3 .alpha. t), but very rarely zero-order release."
Pertinent examples of the above are disclosed in the following references:
U.S. Pat. No. 4,423,099 discloses non-uniform water-insoluble interpenetrating polymer blend compositions comprising a first permeable water swellable polymer substrate interpenetrated in a gradient substantially normal to the substrate surface by a second less permeable condensation polymer to form a diffusion rate controlling membrane therein. The resulting polymer blend is such that the concentration of the condensation polymer increases from 0% at the inner surface of the water swellable polymer to about 100% at the outer surface of the water swellable polymer. Such compositions are useful as polymers with reduced permeabilities for water and organic solvents and therefore for the controlled delivery of active ingredients such as fragrances and bio-affecting agents into air or aqueous environments, or in a membrane separation processes.
U.S. Pat. No. 4,177,056 discloses a controlled, sustained release composition comprising a pharmaceutically, insecticidally or herbicidally effective agent and a water-insoluble hydrophilic gel comprising: (A) about 30 to about 90% of a hydrophilic (a) polymer of identical or different water-soluble mono-olefinic monomers, or (b) copolymer of the water-soluble monomers with 1 to 70% of water-insoluble, identical or different mono-olefinic monomers, which polymer or copolymer is cross linked with (B) about 10 to about 70% of a terminal diolefinic hydrophobic macromer having a molecular weight from about 400 to about 8000.
U.S. Pat. No. 4,138,475 discloses a sustained release pharmaceutical composition consisting of a hard gelatine capsule containing film coated spheroids, the spheriods comprising propranolol or a pharmaceutically acceptable salt thereof, in admixture with a non-water swellable microcrystalline cellulose, with the spheroids having a film coat comprising ethylcellulose optionally together with hydroxypropyl methylcellulose and/or a plasticizer.
U.S. Pat. No. 3,845,770 issued to Theeuwes and Higuchi and well known to the prior art, describes an osmotic device for the zero-order release of an active agent. The osmotic device disclosed in this patent consists of an active agent enclosed in a semi-permeable wall. The semi-permeable wall is permeable to the passage of an external fluid but is substantially impermeable to the passage of the active agent in solution with the external fluid. An osmotic passageway is provided through the wall to deliver the solution of the active agent in the external fluid to the environment. The patent thus teaches the use of osmotic delivery of the active agent solution through a specially constructed passageway instead of delivery via diffusion through a membrane.
U.S. Pat. No. 4,327,725 describes a useful variation of the basic osmotic device. Patentees teach how to enhance the delivery kinetics of the basic osmotic pump via use of a hydrogel layer inside the semi-permeable membrane. The structure of the device consists of an active agent enclosed in a hydrogel layer which is enclosed by a semi-permeable membrane. The semi-permeable membrane allows diffusion of external fluid to inside but does not allow the diffusion of the solution of active agent in the external fluid to the surrounding environment. The hydrogel swells with absorption of external fluid and exerts pressure on the solution of active agent in the external fluid. The solution of the active agent in the external fluid is then delivered to the surrounding media through a single specially constructed passageway through the hydrogel layer and the membrane.
It is claimed that the variation described in U.S. Pat. No. 4,327,725 is particularly useful in case of drugs which are insoluble in the external fluid. The osmotic passageway in the device described in this patent is created by drilling a hole through the semi-permeable wall to connect the active agent compartment with the exterior of the device. A laser-machine is utilized to drill precise holes. This procedure is cumbersome and requires a considerable development effort to tailor the delivery system to each individual drug or active agent.
In case of all osmotic devices, whether a swellable polymer is utilized or not, the delivery mode is the release of the active agent through a specially constructed passageway/hole instead of diffusion through a membrane.